Sex-dependent gene expression during puberty has potential mechanistic implications for the development of major...

Major Depressive Disorder (MDD) is a complex illness with heterogeneous symptom profiles, affecting 5% of the global population. Recent molecular studies across biological systems suggest that the manifestations of MDD are significantly shaped by sex. In response, this narrative review organizes up-to-date findings on sex-specific, MDD-related gene expression into multiple biological systems-primarily available from adult human and rodent studies. This adult-centric focus highlights a critical gap: when and how sex-dependent, MDD-associated gene expression patterns emerge, and contribute to adult manifestations. We identify puberty as a sensitive developmental window during which sex-dependent gene expression and regulatory patterns may emerge and carry their impacts into adulthood. We define this as a sex-specific framework established during puberty. To address the "how," we synthesize empirical evidence on the molecular mechanisms associated with the emergence and long-term influence of this framework. Finally, we explore how perturbations acting on this framework may further bifurcate expression patterns and ultimately give rise to the sex-divergent manifestations of MDD observed in adulthood. Overall, this review positions puberty as a key developmental window and calls for future sex-stratified functional genomic studies that span the pubertal timeline.